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Kooner J.S.,Imperial College London | Saleheen D.,Center for Non Communicable Diseases Pakistan | Saleheen D.,University of Cambridge | Sim X.,National University of Singapore | And 80 more authors.
Nature Genetics

We carried out a genome-wide association study of type-2 diabetes (T2D) in individuals of South Asian ancestry. Our discovery set included 5,561 individuals with T2D (cases) and 14,458 controls drawn from studies in London, Pakistan and Singapore. We identified 20 independent SNPs associated with T2D at P < 10 -4 for testing in a replication sample of 13,170 cases and 25,398 controls, also all of South Asian ancestry. In the combined analysis, we identified common genetic variants at six loci (GRB14, ST6GAL1, VPS26A, HMG20A, AP3S2 and HNF4A) newly associated with T2D (P = 4.1 × 10 -8 to P = 1.9 × 10 -11). SNPs at GRB14 were also associated with insulin sensitivity (P = 5.0 × 10 -4), and SNPs at ST6GAL1 and HNF4A were also associated with pancreatic beta-cell function (P = 0.02 and P = 0.001, respectively). Our findings provide additional insight into mechanisms underlying T2D and show the potential for new discovery from genetic association studies in South Asians, a population with increased susceptibility to T2D. © 2011 Nature America, Inc. All rights reserved. Source

Ahmad S.,Lund University | Zhao W.,University of Pennsylvania | Renstrom F.,Lund University | Rasheed A.,Center for Non Communicable Diseases Pakistan | And 24 more authors.
International Journal of Obesity

Background:Obesity is a complex disease caused by the interplay of genetic and lifestyle factors, but identification of gene-lifestyle interactions in obesity has remained challenging. Few large-scale studies have reported use of genome-wide approaches to investigate gene-lifestyle interactions in obesity.Methods:In the Pakistan Risk of Myocardial Infraction Study, a cross-sectional study based in Pakistan, we calculated body mass index (BMI) variance estimates (square of the residual of inverse-normal transformed BMI z-score) in 14 131 participants and conducted genome-wide heterogeneity of variance analyses (GWHVA) for this outcome. All analyses were adjusted for age, age 2, sex and genetic ancestry.Results:The GWHVA analyses identified an intronic variant, rs140133294, in the FLJ33544 gene in association with BMI variance (P-value=3.1 × 10-8). In explicit tests of gene × lifestyle interaction, smoking was found to significantly modify the effect of rs140133294 on BMI (P interaction =0.0005), whereby the minor allele (T) was associated with lower BMI in current smokers, while positively associated with BMI in never smokers. Analyses of ENCODE data at the FLJ33534 locus revealed features indicative of open chromatin and high confidence DNA-binding motifs for several transcription factors, providing suggestive biological support for a mechanism of interaction.Conclusions:In summary, we have identified a novel interaction between smoking and variation at the FLJ33534 locus in relation to BMI in people from Pakistan. © 2016 Macmillan Publishers Limited. All rights reserved. Source

Ahmad S.,Lund University | Zhao W.,University of Pennsylvania | Renstrom F.,Lund University | Rasheed A.,Center for Non Communicable Diseases Pakistan | And 20 more authors.
BMC Medical Genetics

Background: Multiple genetic variants have been reliably associated with obesity-related traits in Europeans, but little is known about their associations and interactions with lifestyle factors in South Asians. Methods: In 16,157 Pakistani adults (8232 controls; 7925 diagnosed with myocardial infarction [MI]) enrolled in the PROMIS Study, we tested whether: a) BMI-associated loci, individually or in aggregate (as a genetic risk score - GRS), are associated with BMI; b) physical activity and smoking modify the association of these loci with BMI. Analyses were adjusted for age, age2, sex, MI (yes/no), and population substructure. Results: Of 95 SNPs studied here, 73 showed directionally consistent effects on BMI as reported in Europeans. Each additional BMI-raising allele of the GRS was associated with 0.04 (SE = 0.01) kg/m2 higher BMI (P = 4.5 × 10-14). We observed nominal evidence of interactions of CLIP1 rs11583200 (P interaction = 0.014), CADM2 rs13078960 (P interaction = 0.037) and GALNT10 rs7715256 (P interaction = 0.048) with physical activity, and PTBP2 rs11165643 (P interaction = 0.045), HIP1 rs1167827 (P interaction = 0.015), C6orf106 rs205262 (P interaction = 0.032) and GRID1 rs7899106 (P interaction = 0.043) with smoking on BMI. Conclusions: Most BMI-associated loci have directionally consistent effects on BMI in Pakistanis and Europeans. There were suggestive interactions of established BMI-related SNPs with smoking or physical activity. © 2015 Ahmad et al. Source

Huang J.,Lung and Blood Institutes Framingham Heart Study | Sabater-Lleal M.,Karolinska University Hospital | Asselbergs F.W.,University Utrecht | Tregouet D.,University Pierre and Marie Curie | And 95 more authors.

We conducted a genome-wide association study to identify novel associations between genetic variants and circulating plasminogen activator inhibitor-1 (PAI-1) concentration, and examined functional implications of variants and genes that were discovered. A discovery metaanalysis was performed in 19 599 subjects, followed by replication analysis of genome-wide significant (P < 5 × 10-8) single nucleotide polymorphisms (SNPs) in 10 796 independent samples. We further examined associations with type 2 diabetes and coronary artery disease, assessed the functional significance of the SNPs for gene expression in human tissues, and conducted RNA-silencing experiments for one novel association. We confirmed the association of the 4G/5G proxy SNP rs2227631 in the promoter region of SERPINE1 (7q22.1) and discovered genome-wide significant associations at 3 additional loci: chromosome 7q22.1 close to SERPINE1 (rs6976053, discovery P < 3.4 × 10-10); chromosome 11p15.2 within ARNTL (rs6486122, discovery P < 3.0 × 10-8); and chromosome 3p25.2 within PPARG (rs11128603, discovery P = 2.9 × 10-8). Replication was achieved for the 7q22.1 and 11p15.2 loci. There was nominal association with type 2 diabetes and coronary artery disease at ARNTL (P < .05). Functional studies identified MUC3 as a candidate gene for the second association signal on 7q22.1. In summary, SNPs in SERPINE1 and ARNTL and an SNP associated with the expression of MUC3 were robustly associated with circulating levels of PAI-1. Source

Peden J.F.,University of Oxford | Hopewell J.C.,University of Oxford | Saleheen D.,Center for Non Communicable Diseases Pakistan | Saleheen D.,University of Cambridge | And 107 more authors.
Nature Genetics

Genome-wide association studies have identified 11 common variants convincingly associated with coronary artery disease (CAD), a modest number considering the apparent heritability of CAD. All of these variants have been discovered in European populations. We report a meta-analysis of four large genome-wide association studies of CAD, with -4575,000 genotyped SNPs in a discovery dataset comprising 15,420 individuals with CAD (cases) (8,424 Europeans and 6,996 South Asians) and 15,062 controls. There was little evidence for ancestry-specific associations, supporting the use of combined analyses. Replication in an independent sample of 21,408 cases and 19,185 controls identified five loci newly associated with CAD (P < 5- 10 8 in the combined discovery and replication analysis): LIPA on 10q23, PDGFD on 11q22, ADAMTS7-MORF4L1 on 15q25, a gene rich locus on 7q22 and KIAA1462 on 10p11. The CAD-associated SNP in the PDGFD locus showed tissue-specific cis expression quantitative trait locus effects. These findings implicate new pathways for CAD susceptibility. © 2011 Nature America, Inc. All rights reserved. Source

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